Menopause, which is caused by a lowering of the production of female sex hormones that typically occurs at around age 50, but can occur at much earlier or later ages, can generate disorders such as edema, hot flushes (or flashes), attacks of sweating, muscle and possibly joint pain, sleep disturbances, dysphoria, nervousness, mood swings, headache, palpitations (enhanced frequency of heart rate), dry mucous membranes, pain during intercourse and urinary disturbances. Hot flashes or flushing are characterized by a sudden onset of warmth in the face and neck, often progressing to the chest. Episodes generally last several minutes and are evidenced by a visible flushing of the skin. Often such episodes are accompanied by sweating, dizziness, nausea, palpitations and diaphoresis. Such symptoms can disrupt sleep and interfere with quality of life.
Although the cause of hot flashes is not completely understood, they are thought to be a disorder of thermoregulation within the hypothalamus that is a consequence of declining estrogen levels. The administration of female sex hormones, such as estrogen, is effective in palliating these symptoms, but hormone therapy is fraught with undesirable side effects. Four out of five women have disturbing menopause disorders for at least one year and 25% of women have menopause disorders for more than 5 years. Half of all women have severe disorders. Men may also have hot flashes following androgen deprivation therapy (from bilateral orchiectomy or treatment with a gonadotrophin-releasing-hormone agonist) for metastatic prostate cancer. Menopause and perimenopause may also be associated with mood disorders such as depression and anxiety.
Clinicians recognize a distinction among central nervous system illnesses, and there have been many schemes for categorizing mental disorders. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed., Text Revision, (hereinafter, the “DSM-IV-TR™”), published by the American Psychiatric Association, and incorporated herein by reference, provides a standard diagnostic system upon which persons of skill rely. According to the framework of the DSM-IV-TR™, the CNS disorders of Axis I include: disorders diagnosed in childhood (such as, for example, attention deficit disorder or “ADD” and attention deficit/hyperactivity disorder or “ADHD”) and disorders diagnosed in adulthood. CNS disorders diagnosed in adulthood include (1) schizophrenia and psychotic disorders; (2) cognitive disorders; (3) mood disorders; (4) anxiety related disorders; (5) eating disorders; (6) substance related disorders; (7) personality disorders; and (8) “disorders not yet included” in the scheme.
Mood disorders are a group of heterogeneous, typically recurrent illnesses including unipolar (depressive) and bipolar (manic-depressive) disorders that are characterized by pervasive mood disturbances, psychomotor dysfunction, and vegetative symptoms.
In its full syndromal expression, clinical depression manifests as major depressive disorder, with episodic course and varying degrees of residual manifestations between episodes. The mood is typically depressed, irritable, and/or anxious. The patient may appear miserable, with furrowed brows, downturned corners of the mouth, slumped posture, poor eye contact, and monosyllabic (or absent) speech. The morbid mood may be accompanied by preoccupation with guilt, self-denigrating ideas, decreased ability to concentrate, indecisiveness, diminished interest in usual activities, social withdrawal, helplessness, hopelessness, and recurrent thoughts of death and suicide. Sleep disorders are common. In some, the morbid mood is so deep that tears dry up; the patient complains of an inability to experience usual emotions—including grief, joy, and pleasure—and of a feeling that the world has become colorless, lifeless, and dead.
Melancholia (formerly endogenous depression) is characterized by marked psychomotor slowing (of thinking and activity) or agitation (eg, restlessness, wringing of the hands, pressure of speech), weight loss, irrational guilt, and loss of the capacity to experience pleasure. Mood and activity vary diurnally, with a nadir in the morning. Most melancholic patients complain of difficulty falling asleep, multiple arousals, and insomnia in the middle of the night or early morning. Sexual desire is often diminished or lost. Amenorrhea can occur. Anorexia and weight loss may lead to emaciation and secondary disturbances in electrolyte balance.
In atypical depression, reverse vegetative features dominate the clinical presentation; they include anxious-phobic symptoms, evening worsening, initial insomnia, hypersomnia that often extends into the day, and hyperphagia with weight gain. Unlike patients with melancholia, those with atypical depression show mood brightening to potentially positive events but often crash into a paralyzing depression with the slightest adversity. Atypical depressive and bipolar II disorders overlap considerably.
In dysthymic disorder, depressive symptoms typically begin insidiously in childhood or adolescence and pursue an intermittent or low-grade course over many years or decades; major depressive episodes may complicate it (double depression). In pure dysthymia, depressive manifestations occur at a subthreshold level and overlap considerably with those of a depressive temperament: habitually gloomy, pessimistic, humorless, or incapable of fun; passive and lethargic; introverted; skeptical, hypercritical, or complaining; self-critical, self-reproaching, and self-derogatory; and preoccupied with inadequacy, failure, and negative events.
Thorough evaluation of many persons with depression reveals bipolar traits, and as many as one in five patients with a depressive disorder also develops frank hypomania or mania. Most switches from unipolar to bipolar disorder occur within 5 years of the onset of depressive manifestations. Predictors of a switch include early onset of depression (<25 years old), postpartum depression, frequent episodes of depression, quick brightening of mood with somatic treatments (eg, antidepressants, phototherapy, sleep deprivation, electroconvulsive therapy), and a family history of mood disorders for three consecutive generations.
Between episodes, patients with bipolar disorder exhibit depressive moodiness and sometimes high-energy activity; disruption in developmental and social functioning is more common than in unipolar disorder. In bipolar disorder, episodes are shorter (3 to 6 months), age of onset is younger, onset of episodes is more abrupt, and cycles (time from onset of one episode to that of the next) are shorter than in unipolar disorder. Cyclicity is particularly accentuated in rapid-cycling forms of bipolar disorder (usually defined as >=4 episodes/year).
In bipolar I disorder, full-fledged manic and major depressive episodes alternate. Bipolar I disorder commonly begins with depression and is characterized by at least one manic or excited period during its course. The depressive phase can be an immediate prelude or aftermath of mania, or depression and mania can be separated by months or years.
In bipolar II disorder, depressive episodes alternate with hypomanias (relatively mild, nonpsychotic periods of usually <1 week). During the hypomanic period, mood brightens, the need for sleep decreases, and psychomotor activity accelerates beyond the patient's usual level. Often, the switch is induced by circadian factors (eg, going to bed depressed and waking early in the morning in a hypomanic state). Hypersomnia and overeating are characteristic and may recur seasonally (eg, in autumn or winter); insomnia and poor appetite occur during the depressive phase. For some persons, hypomanic periods are adaptive because they are associated with high energy, confidence, and supernormal social functioning. Many patients who experience pleasant elevation of mood, usually at the end of a depression, do not report it unless specifically questioned.
Patients with major depressive episodes and a family history of bipolar disorders (unofficially called bipolar III) often exhibit subtle hypomanic tendencies; their temperament is termed hyperthymic (ie, driven, ambitious, and achievement-oriented).
In cyclothymic disorder, less severe hypomanic and mini-depressive periods follow an irregular course, with each period lasting a few days. Cyclothymic disorder is commonly a precursor of bipolar II disorder. But it can also occur as extreme moodiness without being complicated by major mood disorders. In such cases, brief cycles of retarded depression accompanied by low self-confidence and increased sleep alternate with elation or increased enthusiasm and shortened sleep. In another form, low-grade depressive features predominate; the bipolar tendency is shown primarily by how easily elation or irritability is induced by antidepressants. In chronic hypomania, a form rarely seen clinically, elated periods predominate, with habitual reduction of sleep to <6 hours. Persons with this form are constantly overcheerful, self-assured, overenergetic, full of plans, improvident, overinvolved, and meddlesome; they rush off with restless impulses and accost people.
Anxiety disorders are more common than any other class of psychiatric disorder. Panic attacks are common, affecting >⅓ of the population in a single year. Most persons recover without treatment; a few develop panic disorder. Panic disorder is uncommon, affecting <1% of the population in a 6-month period. Panic disorder usually begins in late adolescence or early adulthood and affects women two to three times more often than men. Phobic disorders involve persistent, unrealistic, yet intense anxiety that, unlike the free-floating anxiety of panic disorder, is attached to external situations or stimuli. Persons who have a phobia avoid such situations or stimuli or endure them only with great distress. However, they retain insight and recognize the excessiveness of their anxiety. In agoraphobia, anxiety about or avoidance of being trapped in situations or places with no way to escape easily if panic develops. Agoraphobia is more common than panic disorder. It affects 3.8% of women and 1.8% of men during any 6-month period. Peak age of onset is the early 20s; first appearance after age 40 is unusual. In specific phobias, clinically significant anxiety is induced by exposure to a specific situation or object, often resulting in avoidance. Specific phobias are the most common anxiety disorders but are often less troubling than other anxiety disorders. They affect 7% of women and 4.3% of men during any 6-month period.
One form of anxiety disorder is social phobia, which is a clinically significant anxiety induced by exposure to certain social or performance situations, often resulting in avoidance. Social phobias affect 1.7% of women and 1.3% of men during any 6-month period. However, more recent epidemiologic studies suggest a substantially higher lifetime prevalence of about 13%. Men are more likely than women to have the most severe form of social anxiety, avoidant personality disorder.
Yet another anxiety disorder is Obsessive-Compulsive Disorder (OCD), a disorder characterized by recurrent, unwanted, intrusive ideas, images, or impulses that seem silly, weird, nasty, or horrible (obsessions) and by urges to do something that will lessen the discomfort due to the obsessions (compulsions). Obsessive-compulsive disorder occurs about equally in men and women and affects 1.6% of the population during any 6-month period.
Posttraumatic Stress Disorder is another anxiety disorder. It is a disorder in which an overwhelming traumatic event is reexperienced, causing intense fear, helplessness, horror, and avoidance of stimuli associated with the trauma. The stressful event involves serious injury or threatened death to the person or others or actual death of others; during the event, the person experiences intense fear, helplessness, or horror. Lifetime prevalence is at least 1%, and in high-risk populations, such as combat veterans or victims of criminal violence, prevalence is reported to be between 3% and 58%.
Acute stress disorder resembles posttraumatic stress disorder in that the person has been traumatized, reexperiences the trauma, avoids stimuli that remind him of the trauma, and has increased arousal. However, by definition, acute stress disorder begins within 4 weeks of the traumatic event and lasts a minimum of 2 days but no more than 4 weeks. A person with this disorder has three or more of the following dissociative symptoms: a sense of numbing, detachment, or absence of emotional responsiveness; reduced awareness of surroundings (eg, being dazed); a feeling that things are not real; a feeling that he is not real; and amnesia for an important part of the trauma. The prevalence of acute stress disorder is unknown but is presumably proportionate to the severity of the trauma and the extent of exposure to the trauma.
Generalized Anxiety Disorder is an excessive, almost daily, anxiety and worry for ≧6 months about a number of activities or events. Generalized anxiety disorder is common, affecting 3 to 5% of the population within a 1-year period. Women are twice as likely to be affected as men. The disorder often begins in childhood or adolescence but may begin at any age.
Anxiety may be secondary to physical disorders, such as neurologic disorders (eg, brain trauma, infections, inner ear disorders), cardiovascular disorders (eg, heart failure, arrhythmias), endocrine disorders (eg, overactive adrenal or thyroid glands), and respiratory disorders (eg, asthma, chronic obstructive pulmonary disease). Anxiety may be caused by use of drugs, such as alcohol, stimulants, caffeine, cocaine, and many prescription drugs. Also, drug withdrawal is commonly associated with anxiety.
An estimated 4 to 5 million Americans (about 2% of all ages and 15% of those >age 65) have some form and degree of cognitive failure (cognitive disorder). Cognitive failure (dysfunction or loss of cognitive functions—the processes by which knowledge is acquired, retained, and used) is most commonly due to delirium (sometimes called acute confusional state) or dementia. It may also occur in association with disorders of affect, such as depression.
Delirium (Acute Confusional State) is a clinical state characterized by fluctuating disturbances in cognition, mood, attention, arousal, and self-awareness, which arises acutely, either without prior intellectual impairment or superimposed on chronic intellectual impairment. Some practitioners use the terms delirium and acute confusional state synonymously; others use delirium to refer to a subset of confused people with hyperactivity. Still others use delirium to refer to full-blown confusion and confusional state to refer to mild disorientation.
Dementia is a chronic deterioration of intellectual function and other cognitive skills severe enough to interfere with the ability to perform activities of daily living. Dementia may occur at any age and can affect young people as the result of injury or hypoxia. However, it is mostly a disease of the elderly, affecting >15% of persons >65 years old and as many as 40% of persons >80 years old. It accounts for more than half of nursing home admissions and is the condition most feared by aging adults.
Alzheimer's Disease is a progressive, inexorable loss of cognitive function associated with an excessive number of senile plaques in the cerebral cortex and subcortical gray matter, which also contains β-amyloid and neurofibrillary tangles consisting of tau protein.
Lewy body dementia may be the second most common dementia after Alzheimer's disease. Lewy bodies are hallmark lesions of degenerating neurons in Parkinson's disease and occur in dementia with or without features of Parkinson's disease. In Lewy body dementia, Lewy bodies may predominate markedly or be intermixed with classic pathologic changes of Alzheimer's disease. Symptoms, signs, and course of Lewy body dementia resemble those of Alzheimer's disease, except hallucinations (mainly visual) are more common and patients appear to have an exquisite sensitivity to antipsychotic-induced extrapyramidal adverse effects.
Cerebrovascular disease can destroy enough brain tissue to impair function. Vascular dementia, which includes impairment due to single, strategically located infarcts or to multiple small infarcts from small or medium-sized vessel disease, is more common in men and generally begins after age 70. It occurs more often in persons who have hypertension and/or diabetes mellitus or who abuse tobacco. Progressive vascular dementia can generally be slowed by controlling blood pressure, regulating blood sugar (90 to 150 mg/dL), and stopping smoking. Some degree of vascular damage is found in up to 20% of autopsies of patients with dementia.
Binswanger's dementia (subcortical arteriosclerotic encephalopathy) is uncommon and involves multiple infarcts in deep hemispheric white matter associated with severe hypertension and systemic vascular disease. Although clinically similar to vascular dementia, Binswanger's dementia may be characterized by more focal neurologic symptoms associated with acute strokes and a more rapid course of deterioration. MRI and CT show areas of leukoencephalopathy in the cerebrum semiovale adjacent to the cortex.
More than 25% of patients with Parkinson's disease have dementia; some estimates are as high as 80% (see Ch. 179). At autopsy, patients with Parkinson's disease may have some of the neuropathologic brain findings and many of the biochemical changes seen in patients with Alzheimer's disease. A less severe subcortical dementia is also associated with Parkinson's disease.
The dementia associated with progressive supranuclear palsy is commonly preceded by other neurologic symptoms, eg, multiple falls, dystonic axial rigidity, retrocollis, supranuclear ophthalmoplegia, dysphagia, and dysarthria.
Patients with Huntington's disease (chorea) may also present with symptoms of dementia, but the diagnosis is usually clarified by the family history, younger age at onset, and the disease's characteristic motor abnormalities. In case of doubt, genetic analysis can be diagnostic.
Pick's disease is a less common form of dementia, affecting the frontal and temporal regions of the cortex. Patients have prominent apathy and memory disturbances; they may show increased carelessness, poor personal hygiene, and decreased attention span. Although the clinical presentation and CT findings in Pick's disease can be quite distinctive, definitive diagnosis is possible only at autopsy. The Klüver-Bucy syndrome can occur early in the course of Pick's disease, with emotional blunting, hypersexual activity, hyperorality (bulimia and sucking and smacking of lips), and visual agnosias.
Frontal lobe dementia syndromes may result from intrinsic pathology, a primary or metastatic tumor, previous surgical manipulation, irradiation to the brain, or severe head trauma. The repeated head trauma in dementia pugilistica, which occurs in professional fighters, appears to link genetically to the 4 allele of apo E.
Normal-pressure hydrocephalus is characterized by a triad of progressive dementia, incontinence, and an unsteady, slow, and wide-based gait. Onset is usually insidious and occurs mostly in late middle or old age. The disease is more common in men and occasionally is related to prior meningitis, subarachnoid hemorrhage, head injury, or neurosurgical interventions. In most cases, evidence of precedent injury is lacking. Normal-pressure hydrocephalus may result from scarring of arachnoid villi over convexities of the brain, which results in slowed absorption of CSF (ceresbrospinal fluid), ventricular dilatation, and frontal lobe motor abnormalities. The laboratory diagnosis is based on high-normal CSF pressure (150 to 200 mm Hg) and CT evidence of ventricular dilatation and narrowed cerebral sulci at the brain's apex without widening of the subarachnoid space. The results of treatment with CSF shunting are inconsistent. The dementia is sometimes reversible; some experts recommend a therapeutic lumbar puncture to remove about 30 mL of CSF. Improvement in gait and cognition for hours or several days suggests the value of shunt placement.
Subdural hematoma can cause a change in mental status, producing coma, delirium, or a dementia syndrome. Cognitive changes may begin any time after blood begins to accumulate and can progress rapidly or slowly, according to the size and location of the hematoma. This chronic syndrome may resemble vascular dementia, with focal neurologic signs and cognitive changes. Removing the hematoma may restore function or prevent further loss of intellectual function. However, some experts believe that after hematomas have exerted pressure on the brain for a long time (perhaps a year or more), removing them does little to improve cognitive function.
The most well-known infectious cause of dementia is Creutzfeldt-Jakob disease, in which memory deficits, electroencephalographic changes, myoclonus, and sometimes ataxia are prominent. The infectious agent is a corrupted protein called a prion that can be acquired genetically, by tissue transplantation, by cannibalism, and apparently by eating products from infected cattle (with mad-cow disease). Most cases occur sporadically. It produces a characteristic spongiform encephalopathy quite different from the changes of Alzheimer's disease. The course is more rapid than that of Alzheimer's disease and usually lasts from 6 to 12 months.
Patients with Gerstmann-Sträussler-Scheinker disease, another dementia with a prion-related cause, typically present with ataxia, followed later by cognitive decline. This syndrome affects younger persons and has a longer duration than Creutzfeldt-Jakob disease.
General paresis, a form of neurosyphilis, was once a common cause of dementia in Western societies. It is still prevalent in developing countries. In addition to intellectual decline, tremors and pupillary changes can occur. The CSF is tested using the fluorescent treponemal antibody (FTA) test. A positive FTA test for syphilis establishes the diagnosis.
AIDS dementia can complicate the later stages of HIV infection. Dementia may be caused by HIV, by the JC virus that causes progressive multifocal leukoencephalopathy, or by a variety of other opportunistic infectious agents, including fungi, bacteria, viruses, or protozoa that can be identified at autopsy. Early manifestations include slowed thinking and expression, difficulty in concentration, and apathy, with preserved insight and few manifestations of depression. Motor movements are slowed; ataxia and weakness may be evident. Reflexes, including the extensor plantar responses, become abnormal. Treatment with zidovudine often induces improvement sometimes verging on the dramatic.
Therefore, there exists a need to develop effective and minimally adverse therapies for the above listed disorders.